The objective of this proposal is to investigate the mechanism by which ethanol acts as a cocarcinogen in nitrosamine carcinogenesis. The nitrosamines to be studied in this program: N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N'-nitrosonornicotine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are constituents of tobacco smoke and in certain cases their carcinogenic activities are known to be increased by chronic ethanol consumption. Our hypothesis is that, depending on the structure of the nitrosamine and the target organ, chronic ethanol pretreatment can increase rates of metabolic activation by enzyme induction, but that simultaneous exposure to ethanol and the nitrosamine can inhibit nitrosamine metabolism. If the net result of these processes is increased metabolic activation, increased carcinogenicity can be expected. To test this hypothesis we will determine the rates of metabolic activation of selected nitrosamines in target organ or cell cultures from ethanol pretreated or control animals. The effects on nitrosamine metabolism of in vitro addition of ethanol to these cultures will also be determined. When increases in nitrosamine activation are indicated in these experiments, we will determine the extents of formation of carcingen-DNA adducts in target organs of ethanol pretreated or control animals. Based on the results of these biochemical assays, the effects of chronic ethanol consumption on the carcinogenicity of selected nitrosamines will be determined. The results of these studies will establish whether ethanol acts as a cocarcinogen in nitrosamine carcinogenesis by increasing target organ metabolic activation. This is significant because alcohol consumption, in combination with smoking, leads to a marked increase in the risk for cancer of the oral cavity, esophagus, and larynx.